Huntington disease (HD) is an incurable terminal disease. Thus, end of life (EOL) concerns are common in these individuals. A quantitative measure of EOL concerns in HD would enable a better understanding of how these concerns impact health-related quality of life. Therefore, we developed new measures of EOL for use in HD.

An EOL item pool of 45 items was field tested in 507 individuals with prodromal or manifest HD. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were conducted to establish unidimensional item pools. Item response theory (IRT) and differential item functioning analyses were applied to the identified unidimensional item pools to select the final items.

EFA and CFA supported two separate unidimensional sets of items: Concern with Death and Dying (16 items), and Meaning and Purpose (14 items). IRT and DIF supported the retention of 12 Concern with Death and Dying items and 4 Meaning and Purpose items. IRT data supported the development of both a computer adaptive test (CAT) and a 6-item, static short form for Concern with Death and Dying.

The HDQLIFE Concern with Death and Dying CAT and corresponding 6-item short form, and the 4-item calibrated HDQLIFE Meaning and Purpose scale demonstrate excellent psychometric properties. These new measures have the potential to provide clinically meaningful information about end-of-life preferences and concerns to clinicians and researchers working with individuals with HD. In addition, these measures may also be relevant and useful for other terminal conditions.

In many plant species, including chrysanthemum, a strong positive correlation between internode length and DIF [difference between day (DT) and night (NT) temperature] has been observed. However, Langton and Cockshull (1997. Scientia Horticulturae 69: 229-237) reported no such relationship and showed that absolute DT and NT explained internode length rather than DIF. To investigate these conflicting results and to clarify the validity of the DIF concept, cut chrysanthemums (Chrysanthemum 'Reagan Improved') were grown in growth chambers at all 16 combinations of four DT and four NT (16, 20, 24 and 28 degrees C) with a 12 h day length. Length of internode 10, number of internodes and stem length were measured on days 5, 10, 17, 22 and 27 after starting the temperature treatments. Internode length on day 10 showed a positive linear relationship with DIF (R2 = 0.64). However, when internodes had reached their final length in all treatments (day 27), a much stronger positive linear relation was observed (R2 = 0.81). A model to predict final internode length was developed based on the absolute DT and NT responses: both responses were optimum curves and no significant interaction between DT and NT occurred [final internode length (mm) = -32.23 + 3.56DT + 1.08NT - 0.0687DT2 - 0.0371NT2; R2 = 0.91, where TD is day temperature and TN is night temperature]. It is shown that DIF can predict final internode length only within a temperature range where effects of DT and NT are equal in magnitude and opposite in sign (18-24 degrees C). Internode appearance rate, as well as stem length formed during the experiment, showed an optimum response to DT.

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), -2, and -3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5-20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC50 values of 5.5, 4.6, and 4.2 μM, respectively. On the other hand, the IC50 values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis.

Circulating and bound IgA antibodies can be found in the autoimmune blistering diseases, but their prevalence, clinical relevance and target antigens remain unknown. Thirty-two patients with pemphigus, 73 with bullous pemphigoid and 28 with mucous membrane pemphigoid were studied retrospectively. Direct immunofluorescence (DIF) analysis of IgG, IgA, IgM and C3 was carried out for all cases. Sera were studied by standard indirect immunofluorescence, indirect immunofluorescence on salt-split skin, immunoblotting for bullous pemphigoid and mucous membrane pemphigoid and ELISA for pemphigus. With DIF, we found IgA autoantibodies in 22 of all 133 cases. Circulating IgA antibodies to skin were detected in 2 of 3 IgA-DIF-positive patients with pemphigus, in 3 of 6 with bullous pemphigoid, and in 6 of 13 with mucous membrane pemphigoid. We confirm that the IgA reactivity is more frequently associated with mucous membrane involvement, especially in cases without critical involvement (5/8). The role of IgA and its antigenic specificity in these diseases remain unclear.

In this paper the main emphasis is laid on presenting an up-to-date description of the relationships between stimulus-related cochlear potentials: cochlear microphonic (CM) and summating potential (SP) and the preceding mechanical events. To this end, CM and SP (both DIF and AVE SP) magnitude functions, obtained with the differential electrode technique, are shown from various turns of the guinea pig's cochlea as recorded at a constant stapes displacement. The similarity between these curves and corresponding basilar membrane displacement functions is considered. The influence upon CM recording of the distributed nature of the generators, as well as the presence of strong nonlinear effects is discussed.

OBJECTIVE

This study compared self-reported fatigue between 7-day and 4-week time frames and explored factors that affect patients' responses.

METHODS

Two hundred and sixteen cancer patients completed either 7-day or 4-week version of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Cochran-Mantel-Haenszel statistics and Cochran-Armitage trend tests were used to assess the association between time frame and item scores. Information function curves at both item and scale levels were depicted to evaluate the precision along the fatigue continuum. Differential item functioning (DIF) was used to examine the stability of the psychometric properties between time frames.

RESULTS

Time frame did not influence patients' item responses. Examination of information function curves at item level did not clearly favor either time frame. At the scale level, the 7-day time frame was slightly more precise overall than the 4-week time frame. No item demonstrated DIF between time frames. Neither gender nor fatigue severity had an impact on above results.

CONCLUSIONS

This study suggests 7-day and 4-week time frame are equally appropriate in measuring fatigue, preference might be given to the more informative 7-day time frame. However, substantive considerations regarding the appropriate time frame should outweigh statistical ones.

Differentiation-inducing factors 1-3 (DIFs 1-3), chlorinated alkylphenones identified in the cellular slime mold Dictyostelium discoideum, are considered anti-tumor agents because they inhibit proliferation of a variety of mammalian tumor cells in vitro. Although the anti-proliferative effects of DIF-1 and DIF-3 are well-documented, the precise molecular mechanisms underlying the actions of DIFs have not been fully elucidated. In this study, we examined the effects of DIFs and their derivatives on PAK1, a key serine-threonine kinase, which is activated by multiple ligands and regulates cell proliferation. We examined the effect of DIF derivatives on PAK1 kinase activity in cells. We also examined the effect of DIF-3(+1) derivative on PAK1 kinase activity in vitro, cyclin D1 promoter activity and breast cancer cell proliferation. It was found that some derivatives strongly inhibited PAK1 kinase activity in human breast cancer MCF-7 cells stably over expressing PAK1. Among the derivatives, DIF-3(+1) was most potent, which directly inhibited kinase activity of recombinant purified PAK1 in an in vitro kinase assay. Furthermore, DIF-3(+1) strongly inhibited both cyclin D1 promoter activity and proliferation of MCF-7 and T47D breast cancer cells stably over expressing PAK1 in response to prolactin, estrogen, epidermal growth factor and heregulin. In the present study we propose PAK1 as DIF-3(+1) target mediating its anti-proliferative effect.

This cross-cultural study aimed to assess whether Iranian and Serbian children, and also their parents, perceived the meaning of the items in the KINDL quality of life questionnaire consistently. The sample included 1086 Iranian and 756 Serbian children and adolescents, alongside 1061 and 618 of their parents, respectively. The ordinal logistic regression was used to assess differential item functioning (DIF) of the self and proxy-reports of the two versions of the KINDL, including Kid-KINDL and Kiddo-KINDL, across Iranian and Serbian samples. Statistically significant DIF was flagged for 14 out of 24 (58%) and 20 out of 24 (83%) items in the self-report of the Kid-KINDL and Kiddo-KINDL, respectively. Moreover, 20 out of 24 (83%) in the proxy reports of the both Kid-KINDL and Kiddo-KINDL, showed DIF across two samples. Accordingly, considerable caution is warranted when using the KINDL for cross-cultural comparisons.

Homologous recombination between the circular chromosomes of bacteria can generate chromosome dimers. They are resolved by a recombination event at a specific site in the replication terminus of chromosomes, dif, by dedicated tyrosine recombinases. The reaction is under the control of a cell division protein, FtsK, which assembles into active DNA pumps at mid-cell during septum formation. Previous studies suggested that activation of Xer recombination at dif was restricted to chromosome dimers in Escherichia coli but not in Vibrio cholerae, suggesting that FtsK mainly acted on chromosome dimers in E. coli but frequently processed monomeric chromosomes in V. cholerae. However, recent microscopic studies suggested that E. coli FtsK served to release the MatP-mediated cohesion and/or cell division apparatus-interaction of sister copies of the dif region independently of chromosome dimer formation. Here, we show that these apparently paradoxical observations are not linked to any difference in the dimer resolution machineries of E. coli and V. cholerae but to differences in the timing of segregation of their chromosomes. V. cholerae harbours two circular chromosomes, chr1 and chr2. We found that whatever the growth conditions, sister copies of the V. cholerae chr1 dif region remain together at mid-cell until the onset of constriction, which permits their processing by FtsK and the activation of dif-recombination. Likewise, sister copies of the dif region of the E. coli chromosome only separate after the onset of constriction in slow growth conditions. However, under fast growth conditions the dif sites separate before constriction, which restricts XerCD-dif activity to resolving chromosome dimers.

In lower-income settings, women more often than men justify intimate partner violence (IPV). Yet, the role of measurement invariance across gender is unstudied. We developed the ATT-IPV scale to measure attitudes about physical violence against wives in 1,055 married men and women ages 18-50 in My Hao district, Vietnam. Across 10 items about transgressions of the wife, women more often than men agreed that a man had good reason to hit his wife (3 % to 92 %; 0 % to 67 %). In random split-half samples, one-factor exploratory factor analysis (EFA) (N 1 = 527) and confirmatory factor analysis (CFA) (N 2 = 528) models for nine items with sufficient variability had significant loadings (0.575-0.883; 0.502-0.897) and good fit (RMSEA = 0.068, 0.048; CFI = 0.951, 0.978, TLI = 0.935, 0.970). Three items had significant uniform differential item functioning (DIF) by gender, and adjustment for DIF revealed that measurement noninvariance was partially masking men's lower propensity than women to justify IPV. A CFA model for the six items without DIF had excellent fit (RMSEA = 0.019, CFI = 0.994, TLI = 0.991) and an attitudinal gender gap similar to the DIF-adjusted nine-item model, suggesting that the six-item scale reliably measures attitudes about IPV across gender. Researchers should validate the scale in urban Vietnam and elsewhere and decompose DIF-adjusted gender attitudinal gaps.

Respiratory Syncytial Virus (RSV) causes annual epidemics of respiratory disease particularly affecting infants. The associated airway inflammation is characterized by an intense neutrophilia. This neutrophilic inflammation appears to be responsible for much of the pathology and symptoms. Previous work from our group had shown that there are factors within the airways of infants with RSV bronchiolitis that inhibit neutrophil apoptosis. This study was undertaken to determine if RSV can directly affect neutrophil survival.NEUTROPHILS WERE ISOLATED FROM CITRATED VENOUS BLOOD (COLLECTED FROM HEALTHY ADULT VOLUNTEERS) BY DISCONTINUOUS PLASMA: Percoll gradient centrifugation and, in some experiments, further purified by negative immunomagnetic bead selection. The effect of RSV on neutrophil survival was measured by Annexin V-PE /To-Pro-3 staining and by morphological changes, using Dif-Quick staining of cytospins.Inhibition of neutrophil apoptosis was observed in neutrophils isolated by standard plasma:Percoll gradient when exposed to RSV but not in ultra pure neutrophil preparations. Adding monocytes back to ultra purified preparations restored the effect. The inhibition of apoptosis was observed with both active and UV inactivated virus. The effect is dependent on a soluble factor and appears to be dependent on CD14 receptors on the monocytes.

Differential item functioning (DIF) for an item between two groups is present if, for the same person location on a variable, persons from different groups have different expected values for their responses. Applying only to dichotomously scored items in the popular Mantel-Haenszel (MH) method for detecting DIF in which persons are classified by their total scores on an instrument, Andrich and Hagquist articulated the concept of artificial DIF and showed that as an artifact of the MH method, real DIF in one item favoring one group inevitably induces artificial DIF favoring the other group in all other items. Using the dichotomous Rasch model in which the total score for a person is a sufficient statistic, and therefore justifies classifying persons by their total scores, Andrich and Hagquist showed that to distinguish between real and artificial DIF in an item identified by the MH method, a sequential procedure for resolving items is implied. Using the polytomous Rasch model, this article generalizes the concept of artificial DIF to polytomous items, in which multiple item parameters play a role. The article shows that the same principle of resolving items sequentially as with dichotomous items applies also to distinguishing between real and artificial DIF with polytomous items. A real example and a small simulated example that parallels the real example are used illustratively.

OBJECTIVE

The main aim of this study was to provide evidence of the broad employability of the NEQ with patients of different gender and age with cancer in different phases of the disease and care process, using an Item Response Theory (IRT) approach and investigating Differential Item Functioning (DIF).

METHODS

The NEQ was completed by 762 patients visiting, consecutively, outpatient clinics or admitted to oncology wards. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. The properties of the questionnaire were analyzed by applying IRT to test how well each item of the scale concurs in measuring unmet needs, how reliable the whole scale is, and whether the scale was metrically invariant across gender, age, and phase of the disease.

RESULTS

Results showed that the NEQ performed well in measuring unmet needs and measurement equivalence of the scale across gender, age, and phase of the disease was verified.

CONCLUSIONS

The current study supports the utility and broad employability of the NEQ, thus providing empirical evidence that it is psychometrically sound and metrically equivalent across different groups of cancer patients. As such, the scale could be an effective tool when planning psychosocial interventions to improve the care process and patients' quality of life.

Differential test functioning, or DTF, occurs when one or more items in a test demonstrate differential item functioning (DIF) and the aggregate of these effects are witnessed at the test level. In many applications, DTF can be more important than DIF when the overall effects of DIF at the test level can be quantified. However, optimal statistical methodology for detecting and understanding DTF has not been developed. This article proposes improved DTF statistics that properly account for sampling variability in item parameter estimates while avoiding the necessity of predicting provisional latent trait estimates to create two-step approximations. The properties of the DTF statistics were examined with two Monte Carlo simulation studies using dichotomous and polytomous IRT models. The simulation results revealed that the improved DTF statistics obtained optimal and consistent statistical properties, such as obtaining consistent Type I error rates. Next, an empirical analysis demonstrated the application of the proposed methodology. Applied settings where the DTF statistics can be beneficial are suggested and future DTF research areas are proposed.

DIF and IIF evaluates in vivo bound and circulating autoantibodies and are the preferred methods for diagnosing AIBDs. In pemphigus diseases and dermatitis herpetiformis, the titer of circulating autoantibodies reflects the disease activity. In patients with a classical clinical picture, the DIF confirms the diagnosis. Furthermore, this technique is essential in subtypes of AIBDs with atypical clinical manifestations (eg, no blisters or erosions) or clinically similar presenting manifestations, such as bullous pemphigoid, MMP, or EBA. A direct or indirect SSST is often crucial for the differential diagnosis between subtypes of these diseases, leading to proper treatment for severely affected patients.

This study examined the performance of a proposed iterative Wald approach for detecting differential item functioning (DIF) between two groups when preknowledge of anchor items is absent. The iterative approach utilizes the Wald-2 approach to identify anchor items and then iteratively tests for DIF items with the Wald-1 approach. Monte Carlo simulation was conducted across several conditions including the number of response options, test length, sample size, percentage of DIF items, DIF effect size, and type of cumulative DIF. Results indicated that the iterative approach performed well for polytomous data in all conditions, with well-controlled Type I error rates and high power. For dichotomous data, the iterative approach also exhibited better control over Type I error rates than the Wald-2 approach without sacrificing the power in detecting DIF. However, inflated Type I error rates were found for the iterative approach in conditions with dichotomous data, noncompensatory DIF, large percentage of DIF items, and medium to large DIF effect sizes. Nevertheless, the Type I error rates were substantially less inflated in those conditions compared with the Wald-2 approach.

With no established standard for assessing tobacco dependence (TD) across tobacco products in surveys, the Population Assessment of Tobacco and Health (PATH) Study provides a unique platform for examining the psychometric properties and validity of multiple indicators of tobacco dependence across a range of tobacco products.

A U.S. nationally representative sample from the 32,320 adult Wave 1 interviews with analyses focused on 14,287 respondents who were current established users of tobacco products.

This analysis confirms a single primary latent construct underlying responses to TD indicators for cigarettes, e-cigarettes, cigars, hookah, and smokeless tobacco products. Mutually exclusive past year tobacco-user groups included: cigarette only (n=8689), e-cigarette only (n=437), cigar only (traditional, cigarillo, or filtered) (n=706), hookah only (n=461), smokeless tobacco only (n=971), cigarette plus e-cigarette (n=709), and multiple tobacco product users (n=2314). Differential Item Functioning (DIF) analyses supported use of 16 of the 24 examined TD indicators for comparisons across tobacco users. With cigarette users as a reference (mean=0.0, SD=1.0), we observed a range of TD with hookah (mean=-1.71) and cigar (mean=-1.92) only users being the lowest, and cigarette plus e-cigarette product users being the highest (mean=0.35). Regression models including sociodemographic factors supported concurrent validity with increased product use frequency and TD among cigarette-only (p<0.001), e-cigarette only (p<0.002), cigar (p<0.001), hookah only (p<0.001), and smokeless tobacco users (p<0.001).

The PATH Study Adult Wave 1 Questionnaire provided psychometrically valid measures of TD that enables future regulatory investigations of nicotine dependence across tobacco products.

BACKGROUND

Pneumonia is common in children and mostly caused by many pathogens. The aim of this study was to investigate whether the incidence of pediatric mycoplasma pneumoniae (MP) pneumonia and respiratory syncytial virus (RSV) pneumonia was associated with meteorological factors in Hangzhou, China.

METHODS

A total of 36500 pneumonia patients were recruited to participate in the study. Nasopharyngeal swabs were collected for the detection of MP and RSV using real-time polymerase chain reaction (RT-PCR) and direct immunofluorescence (DIF) assays, respectively. We used a distributed lag non-linear model (DLNM) to evaluate the correlations between the MP/RSV incidence and meteorological factors.

RESULTS

The detection rates of MP and RSV were 18.4% and 10.4%, respectively. There was a positive correlation between temperature and the MP infection rate, but RSV infection rate was negatively associated with temperature. Moreover, the impact of temperature on infection with RSV presented evident lag and cumulative effects. There was also an evident lag effect of temperature on the infection rate of MP; however, there was no evident cumulative effect.

CONCLUSIONS

In this study, the results showed meteorological factors play an important role in the incidence of these two pathogens. All these results can provide the laboratory basis for the early diagnosis and treatment of pneumonia in children.

Cells of Chlamydomonas reinhardtii differentiate into gametes under conditions of nitrogen (N) starvation, expressing the genes for the N-adaptation program and the gamete program. To investigate the regulatory networks of transcription among the N-starvation-inducible genes, we examined the gene expression in dif mutants, affecting gametic differentiation. In a conditional mutant, difdifdifferentiate into gametes at all, but the induction of only four genes (FUS1, NSG3, NSG6 and NSG7) related to the gamete program was impaired. The results suggest that Dif3 regulates putative N-starvation signal transduction pathways downstream of a master regulator, Dif2. We also examined a light-dependent laboratory strain that was unable to become gametes in the dark. The 'pre-gametes' placed in the dark, however, could induce normally all of the 21 genes, suggesting that light is required for the gametic differentiation at the translational and/or post-translational levels.

This study has explored the relation between dance achievement and alexithymia in a larger Swedish population sample (Swedish Twin Registry) with a study sample of 5431 individuals. Dance achievement (CAQ) was assessed in relation to Alexithymia (Toronto Alexithymia Scale, TAS-20) including the three subscales: Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF), and Externally Oriented Thinking (EOT). The results show a significant negative association between the TAS subscale (EOT) and creative achievement in dance. A high EOT score corresponds to poor ability to communicate feelings to the environment. There was no consistent association between the other factors DIF and DDF and dance achievement. Dance activity and training seem to be involved in the body's emotional interplay with others. Embodied cognition, emotional perception, and action are discussed as factors relevant to measuring the skill of a dancer.

The innate immune response tends to become hyperactive and proinflammatory in older organisms. We investigated connections between activity of the immune-related genes and aging using the Drosophila model. A hallmark of Drosophila immunity is the production of antimicrobial peptides (AMP), whose expression is triggered via activation of the Toll and Imd immune pathways and regulated by NF-ĸB-like transcription factors, Dif/Dorsal and Relish. It was previously shown that overexpression of the upstream component of the immune pathways shortens lifespan via activation of the Relish-dependent immune response. Here we show that direct overexpression of the Relish target AMP genes broadly at high levels or in the fat body induced apoptosis, elicited depolarization of the mitochondria and significantly shortened lifespan. Underexpression of Relish in the fat body beginning in the second half of lifespan prevented overactivation of AMPs and extended longevity. Unlike infection-induced responses, the age-related increase in AMPs does not require the upstream recognition/transduction module of the Imd pathway. It does however require downstream elements, including Relish and Ird5, a component of the downstream IKK complex. Together, these results established causal links between high-level production of antimicrobial peptides and longevity.

BACKGROUND

The subcellular distribution of prorenin receptor and adaptor protein ATP6AP2 may affect neurogenesis. In this study, we hypothesized that ATP6AP2 expression and subcellular relocalization from caveolae/lipid raft microdomains (CLR-Ms) to intracellular sites may correlate with neuronal differentiation (Neu-Dif) of adipose-derived mesenchymal stem cells (ADSCs).

METHODS

Human ADSCs isolated from 24 healthy donors and 24 patients with neurological disorders (ND) were cultured and induced for Neu-Dif. The mechanism of action of ATP6AP2 and the impact of its localization within the plasma membrane (particularly CLR-Ms) and intracellular sites on several pathways (mitogen-activated protein kinase, Wnt(s) signaling and others) and intracellular calcium and exosome release were evaluated. The impact of CLR-Ms on ATP6AP2 or vice versa was determined by pharmacological disruption of CLR-Ms or siATP6AP2 assays.

RESULTS

In patients with ND, loss of ATP6AP2 from CLR-Ms correlated with an inhibition of Neu-Dif and signaling. However, its relocalization in CLR-Ms was positively correlated to induction of Neu-Dif in healthy subjects. An apparent switch from canonical to noncanonical Wnt signaling as well as from caveolin to flotillin occurs concurrently with the increases of ATP6AP2 expression during neurogenesis. Stimulation by renin activates ERK/JNK/CREB/c-Jun but failed to induce β-catenin. Wnt5a enhanced the renin-induced JNK responsiveness. Gα proteins crosslink ATP6AP2 to caveolin where a switch from Gαi to Gαq is necessary for Neu-Dif. In ATP6AP2-enriched CLR-Ms, the release of exosomes was induced dependently from the intracellular Ca2+ and Gαq. Pharmacological disruption of CLR-M formation/stability impairs both ATP6AP2 localization and Neu-Dif in addition to reducing exosome release, indicating an essential role of ATP6AP2 enrichment in CLR-Ms for the induction of Neu-Dif. The mechanism is dependent on CLR-M dynamics, particularly the membrane fluidity. Knockdown of ATP6AP2 inhibited Neu-Dif but increased astrocytic-Dif, depleted ATP6AP2/flotillin/Gαq but accumulated caveolin/Gαi in CLR-Ms, and blocked the activation of JNK/ERK/c-Jun/CREB/exosome release. siATP6AP2 cells treated with sphingomyelinase/methyl-β-cyclodextrin reversed the levels of caveolin/flotillin in CLR-Ms but did not induce Neu-Dif, indicating the crucial relocalization of ATP6AP2 in CLR-Ms for neurogenesis. Treatment of ND-derived cells with nSMase showed reversibility in ATP6AP2 abundance in CLR-Ms and enhanced Neu-Dif.

CONCLUSIONS

This study gives evidence of the determinant role of CLR-M ATP6AP2 localization for neuronal and oligodendrocyte differentiation involving mechanisms of switches from Gαi/caveolin/canonical to Gαq/flotillin/PCP, the ERK/JNK pathway and Ca2+-dependent release of exosomes and as a potential target of drug therapy for neurodegenerative disorders.